Responsive Therapy for Psychiatric Disorders

ABSTRACT

An implantable medical device is capable of delivering a form of therapy (e.g., electrical stimulation) to a region of the cingulate cortex of a patient&#39;s brain to treat a neurological event, condition or disorder, especially an event, condition, or disorder that is psychiatric in nature, such as depression, bipolar disorder, anxiety and obsessive-compulsive disorders, post-traumatic stress disorder, addiction, schizophrenia, and autism and other developmental disorders. The apparatus is also capable of detecting a signal corresponding to a characteristic of the psychiatric disorder. Methods of using the apparatus are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. Ser. No. 10/941,759, filed Sep. 14, 2004.U.S. Ser. No. 10/941,759 is incorporated by reference herein in theentirety.

FIELD OF THE INVENTION

The invention relates to systems and methods for treating braindisorders, and more particularly to treating neuropsychiatric disordersand related diseases with automatically delivered therapies.

BACKGROUND OF THE INVENTION

Severe affective and behavioral psychiatric disorders affect 5 to 10million adults in the United States and are the leading cause ofdisability in North America and Europe. Men and women of all ages andraces are at risk for mental illness and for the associated morbidityand societal cost. Although psychopharmacological therapy provides atleast partial relief for between 70 to 90% of persons suffering frommajor depression, bipolar disorder (BPD), obsessive-compulsive disorder(OCD) and panic and other severe anxiety disorders; others are nothelped or experience unacceptable medication related side effects. Thoseexperiencing schizophrenia, episodic behavioral disorders,post-traumatic stress disorder (PTSD), addictions, and the behavioraland social disorders associated with autism and pervasive developmentaldisorders are less often helped by pharmacotherapy or psychotherapy. Theeconomic cost of untreated mental illness is more than 100 billiondollars each year in the United States.

Accordingly, new treatments are clearly needed for those whose symptomspersist and for those not tolerating therapy, as well as to relieve thesocietal burden created by untreated and undertreated mental illness.

Major depression is a serious and persistent medical illness affecting9.9 million American adults, or approximately 5 percent of the adultpopulation in a given year. Among all medical illnesses, majordepression is the leading cause of disability in the U.S. and many otherdeveloped countries. About three-fourths of those who experience a firstepisode of depression will have at least one other episode in theirlives and some individuals have several episodes in the course of ayear. If untreated, episodes commonly last anywhere from six months to ayear. Left untreated, depression can lead to suicide.

Treatment typically includes medications, psychotherapy, andelectroconvulsive therapy (ECT) used singly or in combination. Althoughmild to moderate depression can often be treated successfully withmedications or psychotherapy used alone, severe depression usuallyrequires a combination of psychotherapy and medication. ECT is highlyeffective for treatment resistant or treatment intolerant severedepression and to relieve symptoms such as psychosis or thoughts ofsuicide. However, ECT often requires repeated therapies and can causepersistent and troubling memory disturbances.

Bipolar disorder is another other common major psychiatric disordersthat may be treatment resistant. Bipolar disorder is a chronic disorderthat affects 2.3 million adult Americans. Bipolar disorder ischaracterized by episodes of mania and depression that can last fromdays to months. Persons with bipolar disorder usually require lifelongtreatment, and recovery between episodes is often poor. Generally, thosewho suffer from bipolar disorder have symptoms of both mania anddepression (sometimes at the same time). Medications are available totreat depression or mania and provide mood stabilization. However, mostpersons with bipolar disorder require multiple medications to achievesymptom relief. Thus, persons with bipolar disease are at risk formedication related side effects that prompt some to discontinue therapy.Others who are compliant with therapy do not achieve complete symptomrelief.

Obsessive-Compulsive Disorder (OCD) affects 2 to 3% of the population asconfirmed in the U.S. and international epidemiological studies, and istwo to three times more common than schizophrenia and bipolar disorder.Obsessions and compulsive behaviors can cause suffering and severerestrictions on life activities. Response to treatment varies fromperson to person. Most people treated with effective medications findtheir symptoms reduced by about 40 percent to 50 percent. Although suchsymptom relief is welcome, freedom from symptoms is rarely achieved andonly a small number of people are fortunate to go into total remission.Only one fifth of patients achieve full remission within one decade ofthe onset of the illness and two-thirds continue to experience symptomsdespite treatment with selective serotonin reuptake inhibitor drugs(SSRIs) and the use of behavior therapy.

Some persons with chronic, treatment resistant mental illness haveturned to surgical therapies. Frontal lobotomy was championed in thelate 1930s to the 1970s. Although effective in some cases, the surgerywas crude, not standardized and involved destruction of a large regionof the frontal lobe. The procedure was largely abandoned because ofunacceptable surgical complications and because of ethical violations inits application. A few centers continued to offer surgical therapy tothe most devastated patients. The National Commission for the Protectionof Human Subjects of Biomedical and Behavioral Research (1977) indicatedthat more than half of 400 surgeries performed annually between 1971 and1973 for psychiatric indications were efficacious, and there is reasonto believe efficacy has improved since then.

Recently, neurosurgeons have developed more precise surgical proceduresto treat psychiatric disorders, including depression and, more commonly,obsessive-compulsive disorder. The majority of these procedures involvetargeted ablative procedures. In these refractory patients, stereotacticsurgical interventions performed include subcaudate tractotomy, limbicleucotomy, capsulotomy, and cingulotomy. Cingulotomy is the mostcommonly performed procedure. Twenty-five to 30% of patients treatedwith cingulotomy experience improvement at more than 2 years follow-up.However, these procedures are associated with risks including changes inpersonality and development of epilepsy. Other adverse effects includefrontal lobe deficit in as many as 30% with fatigue, emotional blunting,emotional incontinence, indifference, low initiative, disinhibition andimpaired judgment. These procedures carry the risk that the lesion willbe malpositioned, which may require repeated surgery to extend the sizeof the lesion. Thus, concerns about safety and the irreversibility ofsurgical procedures remain.

Due to the limited response to lesion-based surgery and concerns aboutadverse effects, some investigators have turned to electricalstimulation therapy. Building on the experience from essential tremorand Parkinson's Disease, investigators have utilized commerciallyavailable deep brain stimulators implanted in the anterior internalcapsule bilaterally and have reported symptomatic improvement in OCD.However, because of the stimulation requirements for clinical response(4 to 10.5V, impedance 700 ohms, pulse width 210 microseconds, 100 Hzfrequency) the stimulator battery requires replacement every 5 to 12months, limiting patient acceptance for this therapy.

The neuroanatomical base for many psychiatric disorders is betterunderstood because of advances in functional neuroimaging, such asPositron Emission Tomography (PET), Magnetic Resonance Imaging (MRI),Functional MRI (fMRI), and Magnetoencephalography (MEG). In addition,clinical observations after destructive brain lesions identify regionssubserving specific aspects of behavior and affect. The cingulate cortexis a large structure around the rostrum of the corpus callosum that hasextensive projections with the amygdala, periaqueductal grey, ventralstriatum, orbitofrontal and anterior insular cortices. This structureand its interconnections are intimately involved in mood and behavior.Dysfunction of the cingulate and disruption of its connections has beenimplicated in a number of psychiatric disorders. As noted above,cingulotomy is the most common psychosurgery procedure for majordepression and obsessive-compulsive disorder. This procedure iseffective for many but carries considerable risk for post-surgicalchanges in personality and motivation, and for post-operative epilepsy.

The size and complexity of the cingulate cortex poses a challenge intargeting the region responsible for specific psychiatric and behavioraldisorders. The cingulate is divided functionally into regions concernedwith affect and cognition. Affect is mediated in cingulate regions 25,33 and rostral area 24 that are extensively interconnected to theamygdala and periaqueductal grey, as well as autonomic brainstem nuclei.The cognitive division resides in caudal areas 24′ and 32′, and incingulate motor areas in the cingulate sulcus and nociceptive cortex.Individuals with disturbances to the cingulate cortex, such as thosewith cingulate onset epilepsy, often display sociopathic behavior.Elevated anterior cingulate activity may contribute to tics,obsessive-compulsive behaviors and aberrant social behavior. Reducedcingulate activity can contribute to schizophrenia, behavioral disorderssuch as akinetic mutism, diminished self-awareness and depression, motorneglect and impaired initiation of movement, reduced pain response andabnormal social behavior.

There is a need for a responsive implantable system capable ofameliorating the symptoms of, and in some cases the underlying causesof, various psychiatric disorders.

SUMMARY OF THE INVENTION

Modulation of the function of the cingulate cortex can alleviatesymptoms associated with psychiatric disorders believed to arise becauseof functional or structural abnormalities of this structure. Researchindicates that a number of psychiatric disease are mediated through thecingulate cortex, including major depression, obsessive compulsivedisorder, panic and anxiety disorders, explosive behavior disorder,post-traumatic stress disorder, substance addiction and schizophrenia.Dysfunction of the cingulate cortex is also implicated in the socialdisability associated with autism and pervasive developmental disorders.

In systems, devices and methods according to the present invention,therapy for the psychiatric diseases set forth above is provided bymeans of a device that is able to provide responsive and programmedelectrical stimulation to the cingulate cortex and other relevantportions of the brain and peripheral nervous system.

In an embodiment of the invention, a device is implanted in the craniumand attached to leads with electrodes at the distal end of each lead.The electrodes are placed within or against the entire length ofcingulate cortex, whether in the form of a depth electrode or a subduralelectrode. A single electrode or multiple electrodes may be implanted.

The device has a sensing function that responds to changes in abiological marker. Such biological markers could be changes inelectrical activity, changes in concentration of inhibitory orexcitatory neurochemicals, changes in proteins or other gene products,or changes in temperature or markers of metabolic rate. Sensingelectrodes are placed over the cingulate cortex or at a distance.

Responsive therapy is provided at some location within the cingulatecortex. Such therapy may include a depolarizing electrical stimulation,drug delivery or changes in temperature. In addition, therapy deliverycan be programmed by the physician in response to the patient'ssymptoms. The device also includes the capability for therapy to betriggered by the patient.

Such a device system could provide benefit for those individuals withtreatment resistant psychiatric illness and for those who experiencedrug-related side effects that limit quality of life. In addition, adevice therapy as described above can be anticipated to have a morefavorable safety profile than cortical resection or cortical lesion, andwill be modifiable across individuals and over time and is reversible ifthe desired effects are not achieved.

The precise region of the cingulate cortex over which therapy isoptimally applied may differ from individual to individual and by thepsychiatric or behavioral disorder. The proposed electrode array affordswide coverage of the cingulate. Also, the electrodes over which therapyis applied can be adjusted according to the patient's short andlong-term response.

The device provides continuous monitoring of electrocorticographicsignals. This capability can identify disturbances in brain electricalactivity over the cingulate gyrus, which is a region that cannot beadequately monitored by scalp EEG due to its distance from the recordingelectrodes and the significant filtering effect of skull and scalp. Thisis an especially important capability of the system because psychiatricdisorders are likely to be accompanied by dynamic electrographicdisturbances. This device will also enable continuous monitoring ofother biological markers that may reveal signals of disease and diseasesymptoms. Identifying these biological markers will contribute toknowledge regarding the underlying pathophysiology of these diseases andwill provide information that may open new avenues for targeted therapy.

Direct cortical stimulation of the cingulate cortex using a deviceaccording to the invention provides advantages over resective andlesion-based surgery and over deep-brain stimulation. Targeted corticalstimulation (as opposed to the high amount of energy required to achievesymptom relief from stimulation of anterior capsule electrodes) promiseslonger battery life. As described above, an exemplary device utilizestwo leads of four electrodes each. Using either depth or subdural leads(or a combination of the two), electrodes can be applied over much ofthe cingulate cortex bilaterally. Optimal stimulation electrodes can beconfigured over time as a patient's symptoms are observed. Stimulationmay be quite focal, using adjacent electrodes as anode and cathode, orcan be applied to both left and right cingulate cortices simultaneouslyby utilizing all eight electrodes referred to the can of the device.

Another advantage of the implantable neurostimulator system is thecapacity to apply modifiable stimulation settings. In an embodiment ofthe invention, pulse widths can be set between 40 and 1000 microseconds,pulse frequency may range between 1 and 333 Hz, and current can beadjusted between 0.5 and 12 milliamps. This ensures that patientsreceive the optimal pulse settings without adverse effects. It isreasonable to assume that individual patients will differ in terms ofthe optimal stimulus settings. A practitioner of ordinary skill would beable to make adjustments to these parameters based on clinicalobservations.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features, and advantages of the invention willbecome apparent from the detailed description below and the accompanyingdrawings, in which:

FIG. 1 is a drawing of a neurostimulator device according to theinvention in communication with an exemplary brain hemisphere includingthe cingulate gyrus;

FIG. 2 is a schematic illustration of a patient's head showing theplacement of an implantable neurostimulator according to an embodimentof the invention;

FIG. 3 is a schematic illustration of a patient's cranium showing theimplantable neurostimulator of FIG. 2 as implanted, including a leadextending to the patient's brain;

FIG. 4 is a block diagram illustrating a system context in which animplantable neurostimulator according to the invention is implanted andoperated;

FIG. 5 is a block diagram illustrating the major functional subsystemsof an implantable neurostimulator according to the invention;

FIG. 6 is a drawing of an exemplary brain hemisphere and an exemplarycortical electrode positioned over the cingulate gyrus;

FIG. 7 is a drawing of an exemplary brain hemisphere and an exemplarydepth electrode positioned in the cingulate gyrus;

FIG. 8 is a block diagram illustrating the functional components of thedetection subsystem of the implantable neurostimulator shown in FIG. 5;

FIG. 9 is a block diagram illustrating the components of the waveformanalyzer of the detection subsystem of FIG. 8;

FIG. 10 is a flow chart setting forth an illustrative process performedby hardware functional components of the neurostimulator of FIG. 5 intreating psychiatric disorders according to the invention;

FIG. 11 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat major depression;

FIG. 12 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat bipolar disorder;

FIG. 13 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat anxiety andobsessive-compulsive disorders;

FIG. 14 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat post-traumatic stressdisorder;

FIG. 15 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat addiction;

FIG. 16 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat schizophrenia;

FIG. 17 is a flow chart illustrating a process advantageously used by asystem according to the invention to treat autism and otherdevelopmental disorders; and

FIG. 18 illustrates a set of therapy waveforms for electricalstimulation that may be used by a neurostimulator according to theinvention to treat psychiatric disorders.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below, with reference to detailedillustrative embodiments. It will be apparent that a system according tothe invention may be embodied in a wide variety of forms. Consequently,the specific structural and functional details disclosed herein arerepresentative and do not limit the scope of the invention.

FIG. 1 illustrates, schematically, an implantable neurostimulator device110 in communication with various locations within a patient's brain112, particularly the cingulate gyrus 114. In a system according to theinvention, the neurostimulator device receives signals from thepatient's brain 112 (or other physiological indicators) and responsivelytreats symptoms or conditions of psychological illness.

FIG. 2 depicts an intracranial implantation of the device 110 accordingto the invention, which in one embodiment is a small self-containedresponsive neurostimulator. As the term is used herein, a responsiveneurostimulator is a device capable of detecting or predictingneurological events, such as abnormal electrical activity, and providingelectrical stimulation to neural tissue in response to that activity,where the electrical stimulation is specifically intended to terminatethe abnormal activity, treat a neurological event, prevent an unwantedneurological event from occurring, or lessen the severity or frequencyof certain symptoms of a neurological disorder. As disclosed herein, theresponsive neurostimulator detects abnormal neurological activity bysystems and methods according to the invention.

Preferably, an implantable device according to the invention is capableof detecting or predicting any kind of neurological event that has arepresentative electrographic signature. While the disclosed embodimentis described primarily as responsive to symptoms and conditions presentin psychiatric disorders, it should be recognized that it is alsopossible to respond to other types of neurological disorders, such asepilepsy, movement disorders (e.g. the tremors characterizingParkinson's disease), migraine headaches, and chronic pain. Preferably,neurological events representing any or all of these afflictions can bedetected when they are actually occurring, in an onset stage, or as apredictive precursor before clinical symptoms begin.

In the disclosed embodiment, the neurostimulator is implantedintracranially in a patient's parietal bone 310, in a location anteriorto the lambdoid suture 312 (see FIG. 3). It should be noted, however,that the placement described and illustrated herein is merely exemplary,and other locations and configurations are also possible, in the craniumor elsewhere, depending on the size and shape of the device andindividual patient needs, among other factors. The device 110 ispreferably configured to fit the contours of the patient's cranium 314.In an alternative embodiment, the device 110 is implanted under thepatient's scalp 212 (see FIG. 2) but external to the cranium; it isexpected, however, that this configuration would generally cause anundesirable protrusion in the patient's scalp where the device islocated. In yet another alternative embodiment, when it is not possibleto implant the device intracranially, it may be implanted pectorally(not shown), with leads extending through the patient's neck and betweenthe patient's cranium and scalp, as necessary.

It should be recognized that the embodiment of the device 110 describedand illustrated herein is preferably a responsive neurostimulator fordetecting and treating various psychiatric disorders and relateddisorders by detecting neurophysiological conditions, symptoms, or theironsets or precursors, and preventing and/or relieving such conditionsand symptoms.

In an alternative embodiment of the invention, the device 110 is not aresponsive neurostimulator, but is an apparatus capable of detectingneurological conditions and events and performing actions in responsethereto. The actions performed by such an embodiment of the device 110need not be therapeutic, but may involve data recording or transmission,providing warnings to the patient, or any of a number of knownalternative actions. Such a device will typically act as a diagnosticdevice when interfaced with external equipment, as will be discussed infurther detail below.

The device 110, as implanted intracranially, is illustrated in greaterdetail in FIG. 3. The device 110 is affixed in the patient's cranium 314by way of a ferrule 316. The ferrule 316 is a structural member adaptedto fit into a cranial opening, attach to the cranium 314, and retain thedevice 110.

To implant the device 110, a craniotomy is performed in the parietalbone 310 anterior to the lambdoid suture 312 to define an opening 318slightly larger than the device 110. The ferrule 316 is inserted intothe opening 318 and affixed to the cranium 314, ensuring a tight andsecure fit. The device 110 is then inserted into and affixed to theferrule 316.

As shown in FIG. 3, the device 110 includes a lead connector 320 adaptedto receive one or more electrical leads, such as a first lead 322. Thelead connector 320 acts to physically secure the lead 322 to the device110, and facilitates electrical connection between a conductor in thelead 322 coupling an electrode to circuitry within the device 110. Thelead connector 320 accomplishes this in a substantially fluid-tightenvironment with biocompatible materials.

The lead 322, as illustrated, and other leads for use in a system ormethod according to the invention, is a flexible elongated member havingone or more conductors. As shown, the lead 322 is coupled to the device110 via the lead connector 320, and is generally situated on the outersurface of the cranium 314 (and under the patient's scalp 212),extending between the device 110 and a burr hole 324 or other cranialopening, where the lead 322 enters the cranium 314 and is coupled to adepth electrode (e.g., one of the sensors 512-518 of FIG. 5) implantedin a desired location in the patient's brain. If the length of the lead322 is substantially greater than the distance between the device 110and the burr hole 324, any excess may be urged into a coil configurationunder the scalp 212. As described in U.S. Pat. No. 6,006,124 to Fischellon Dec. 21, 1999, et al. entitled “MEANS AND METHODS FOR THE PLACEMENTOF BRAIN ELECTRODES,” which is hereby incorporated by reference asthough set forth in full herein, the burr hole 324 is sealed afterimplantation to prevent further movement of the lead 322; in anembodiment of the invention, a burr hole cover apparatus is affixed tothe cranium 314 at least partially within the burr hole 324 to providethis functionality.

The device 110 includes a durable outer housing 326 fabricated from abiocompatible material. Titanium, which is light, extremely strong, andbiocompatible, is used in analogous devices, such as cardiac pacemakers,and would serve advantageously in this context. As the device 110 isself-contained, the housing 326 encloses a battery and any electroniccircuitry necessary or desirable to provide the functionality describedherein, as well as any other features. As will be described in furtherdetail below, a telemetry coil may be in the interior of the device 110or provided outside of the housing 326 (and potentially integrated withthe lead connector 320) to facilitate communication between the device110 and external devices.

The neurostimulator configuration described herein and illustrated inFIG. 3 provides several advantages over alternative designs. First, theself-contained nature of the neurostimulator substantially decreases theneed for access to the device 110, allowing the patient to participatein normal life activities. Its small size and intracranial placementcauses a minimum of cosmetic disfigurement. The device 110 will fit inan opening in the patient's cranium, under the patient's scalp, withlittle noticeable protrusion or bulge. The ferrule 316 used forimplantation allows the craniotomy to be performed and fit verifiedwithout the possibility of breaking the device 110, and also providesprotection against the device 110 being pushed into the brain underexternal pressure or impact. A further advantage is that the ferrule 316receives any cranial bone growth, so at explant, the device 110 can bereplaced without removing any bone screws—only the fasteners retainingthe device 110 in the ferrule 316 need be manipulated.

As stated above, and as illustrated in FIG. 4, a neurostimulatoraccording to the invention operates in conjunction with externalequipment. The implantable neurostimulator device 110 is mostlyautonomous (particularly when performing its usual sensing, detection,and stimulation capabilities), but preferably includes a selectablepart-time wireless link 410 to external equipment such as a programmer412. In the disclosed embodiment of the invention, the wireless link 410is established by moving a wand (or other apparatus) havingcommunication capabilities and coupled to the programmer 412 intocommunication range of the implantable neurostimulator device 110. Theprogrammer 412 can then be used to manually control the operation of thedevice, as well as to transmit information to or receive informationfrom the implantable neurostimulator 110. Several specific capabilitiesand operations performed by the programmer 412 in conjunction with thedevice will be described in further detail below.

The programmer 412 is capable of performing a number of advantageousoperations in connection with the invention. In particular, theprogrammer 412 is able to specify and set variable parameters in theimplantable neurostimulator device 110 to adapt the function of thedevice to meet the patient's needs, upload or receive data (includingbut not limited to stored EEG waveforms, parameters, or logs of actionstaken) from the implantable neurostimulator 110 to the programmer 412,download or transmit program code and other information from theprogrammer 412 to the implantable neurostimulator 110, or command theimplantable neurostimulator 110 to perform specific actions or changemodes as desired by a physician operating the programmer 412. Tofacilitate these functions, the programmer 412 is adapted to receiveclinician input 414 and provide clinician output 416; data istransmitted between the programmer 412 and the implantableneurostimulator 110 over the wireless link 410.

The programmer 412 may be used at a location remote from the implantableneurostimulator 110 if the wireless link 410 is enabled to transmit dataover long distances. For example, the wireless link 410 may beestablished by a short-distance first link between the implantableneurostimulator 110 and a transceiver, with the transceiver enabled torelay communications over long distances to a remote programmer 412,either wirelessly (for example, over a wireless computer network) or viaa wired communications link (such as a telephonic circuit or a computernetwork).

The programmer 412 may also be coupled via a communication link 418 to anetwork 420 such as the Internet. This allows any information uploadedfrom the implantable neurostimulator 110, as well as any program code orother information to be downloaded to the implantable neurostimulator110, to be stored in a database 422 at one or more data repositorylocations (which may include various servers and network-connectedprogrammers like the programmer 412). This would allow a patient (andthe patient's physician) to have access to important data, includingpast treatment information and software updates, essentially anywhere inthe world where there is a programmer (like the programmer 412) and anetwork connection. Alternatively, the programmer 412 may be connectedto the database 422 over a trans-telephonic link.

In yet another alternative embodiment of the invention, the wirelesslink 410 from the implantable neurostimulator 110 may enable a transferof data from the neurostimulator 110 to the database 422 without anyinvolvement by the programmer 412. In this embodiment, as with others,the wireless link 410 may be established by a short-distance first linkbetween the implantable neurostimulator 110 and a transceiver, with thetransceiver enabled to relay communications over long distances to thedatabase 422, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such astrans-telephonically over a telephonic circuit, or over a computernetwork).

In the disclosed embodiment, the implantable neurostimulator 110 is alsoadapted to receive communications from an initiating device 424,typically controlled by the patient or a caregiver. Accordingly, patientinput 426 from the initiating device 424 is transmitted over a wirelesslink to the implantable neurostimulator 110; such patient input 426 maybe used to cause the implantable neurostimulator 110 to switch modes (onto off and vice versa, for example) or perform an action (e.g., store arecord of EEG data). Preferably, the initiating device 424 is able tocommunicate with the implantable neurostimulator 110 through acommunication subsystem 530 (FIG. 5), and possibly in the same mannerthe programmer 412 does. The link may be unidirectional (as with themagnet and GMR sensor described below), allowing commands to be passedin a single direction from the initiating device 424 to the implantableneurostimulator 110, but in an alternative embodiment of the inventionis bidirectional, allowing status and data to be passed back to theinitiating device 424. Accordingly, the initiating device 424 may be aprogrammable personal data assistant (PDA) or other hand-held computingdevice, such as a PALM device or POCKET PC. However, a simple form ofinitiating device 424 may take the form of a permanent magnet, if thecommunication subsystem 530 (FIG. 5) is adapted to identify magneticfields and interruptions therein as communication signals.

The implantable neurostimulator 110 (FIG. 1) generally interacts withthe programmer 412 (FIG. 4) as described below. Data stored in a memorysubsystem 526 (FIG. 5) of the device 110 can be retrieved by thepatient's physician through the wireless communication link 410, whichoperates through the communication subsystem 530 of the implantableneurostimulator 110. In connection with the invention, a softwareoperating program run by the programmer 412 allows the physician to readout a history of neurological events detected including EEG informationbefore, during, and after each neurological event, as well as specificinformation relating to the detection of each neurological event (suchas, in one embodiment, the time-evolving energy spectrum of thepatient's EEG). The programmer 412 also allows the physician to specifyor alter any programmable parameters of the implantable neurostimulator110. The software operating program also includes tools for the analysisand processing of recorded EEG records to assist the physician indeveloping optimized seizure detection parameters for each specificpatient.

In an embodiment of the invention, the programmer 412 is primarily acommercially available PC, laptop computer, or workstation having a CPU,keyboard, mouse and display, and running a standard operating systemsuch as MICROSOFT WINDOWS, LINUX, UNIX, or APPLE MAC OS. It is alsoenvisioned that a dedicated programmer apparatus with a custom softwarepackage (which may not use a standard operating system) could bedeveloped.

When running the computer workstation software operating program, theprogrammer 412 can process, store, play back and display on the displaythe patient's EEG signals, as previously stored by the implantableneurostimulator 110 of the implantable neurostimulator device.

The computer workstation software operating program also has thecapability to simulate the detection and prediction of abnormalelectrical activity and other symptoms of psychiatric disorders.Furthermore, the software operating program of the present invention hasthe capability to allow a clinician to create or modify apatient-specific collection of information comprising, in oneembodiment, algorithms and algorithm parameters for specific activitydetection. The patient-specific collection of detection algorithms andparameters used for neurological activity detection according to theinvention will be referred to herein as a detection template orpatient-specific template. The patient-specific template, in conjunctionwith other information and parameters generally transferred from theprogrammer to the implanted device (such as stimulation parameters, timeschedules, and other patient-specific information), make up a set ofoperational parameters for the neurostimulator.

Following the development of a patient-specific template on theprogrammer 412, the patient-specific template would be downloadedthrough the communications link 410 from the programmer 412 to theimplantable neurostimulator 110.

The patient-specific template is used by a detection subsystem 522 andCPU 528 (FIG. 5) of the implantable neurostimulator 110 to detectconditions indicating treatment should be administered, and can beprogrammed by a clinician to result in responsive stimulation of thepatient's brain, as well as the storage of EEG records before and afterthe detection, facilitating later clinician review.

Preferably, the database 422 is adapted to communicate over the network420 with multiple programmers, including the programmer 412 andadditional programmers 428, 430, and 432. It is contemplated thatprogrammers will be located at various medical facilities andphysicians' offices at widely distributed locations. Accordingly, ifmore than one programmer has been used to upload EEG records from apatient's implantable neurostimulator 110, the EEG records will beaggregated via the database 422 and available thereafter to any of theprogrammers connected to the network 420, including the programmer 412.

FIG. 5 is an overall block diagram of the implantable neurostimulatordevice 110 used for measurement, detection, and treatment according tothe invention. Inside the housing of the neurostimulator device 110 areseveral subsystems making up the device. The implantable neurostimulatordevice 110 is capable of being coupled to a plurality of sensors 512,514, 516, and 518 (each of which may be individually or togetherconnected to the implantable neurostimulator device 110 via one or moreleads), which in an embodiment of the invention are electrodes used forboth sensing and stimulation as well as the delivery of other treatmentmodalities. In the illustrated embodiment, the coupling is accomplishedthrough a lead connector. Although four sensors are shown in FIG. 5, itshould be recognized that any number is possible, and in the embodimentdescribed in detail below, eight electrodes are used as sensors. Infact, it is possible to employ an embodiment of the invention that usesa single lead with at least two electrodes, or two leads each with asingle electrode (or with a second electrode provided by a conductiveexterior portion of the housing in one embodiment), although bipolarsensing between two closely spaced electrodes on a lead is preferred tominimize common mode signals including noise.

The sensors 512-518 are in contact with the patient's brain or areotherwise advantageously located to receive EEG signals or provideelectrical stimulation or another therapeutic modality. Each of thesensors 512-518 is also electrically coupled to a sensor interface 520.Preferably, the electrode interface is capable of selecting eachelectrode as required for sensing and stimulation; accordingly theelectrode interface is coupled to a detection subsystem 522 and atherapy subsystem 524 (which, in various embodiments of the invention,may provide electrical stimulation and other therapies). The sensorinterface 520 may also provide any other features, capabilities, oraspects, including but not limited to amplification, isolation, andcharge-balancing functions, that are required for a proper interfacewith neurological tissue and not provided by any other subsystem of thedevice 110.

In an embodiment of the invention in which electrographic signals arereceived by electrodes and analyzed, the detection subsystem 522includes and serves primarily as an EEG waveform analyzer. It will berecognized that similar principles apply to the analysis of other typesof waveforms received from other types of sensors. Detection isgenerally accomplished in conjunction with a central processing unit(CPU) 528. The waveform analyzer finction is adapted to receive signalsfrom the sensors 512-518, through the sensor interface 520, and toprocess those EEG signals to identify abnormal neurological activitycharacteristic of a disease or symptom thereof. One way to implementsuch EEG analysis functionality is disclosed in detail in U.S. Pat. No.6,016,449 to Fischell et al., incorporated by reference above.Additional inventive methods are described in U.S. Pat. No. 6,810,285 toPless et al., filed on Jun. 28, 2001 and entitled “SEIZURE SENSING ANDDETECTION USING AN IMPLANTABLE DEVICE,” of which relevant details willbe set forth below (and which is also hereby incorporated by referenceas though set forth in full). The detection subsystem may optionallyalso contain further sensing and detection capabilities, including butnot limited to parameters derived from other physiological conditions(such as electrophysiological parameters, temperature, blood pressure,neurochemical concentration, etc.). In general, prior to analysis, thedetection subsystem performs amplification, analog-to-digitalconversion, and multiplexing functions on the signals in the sensingchannels received from the sensors 512-518.

The therapy subsystem 524 is capable of applying electrical stimulationor other therapies to neurological tissue. This can be accomplished inany of a number of different manners. For example, it may beadvantageous in some circumstances to provide stimulation in the form ofa substantially continuous stream of pulses, or on a scheduled basis.Preferably, therapeutic stimulation is provided in response to abnormalneurological events or conditions detected by the waveform analyzerfunction of the detection subsystem 522. As illustrated in FIG. 5, thetherapy subsystem 524 and the EEG analyzer function of the detectionsubsystem 522 are in communication; this facilitates the ability oftherapy subsystem 524 to provide responsive electrical stimulation andother therapies, as well as an ability of the detection subsystem 522 toblank the amplifiers while electrical stimulation is being performed tominimize stimulation artifacts. It is contemplated that the parametersof a stimulation signal (e.g., frequency, duration, waveform) providedby the therapy subsystem 524 would be specified by other subsystems inthe implantable device 110, as will be described in further detailbelow.

In accordance with the invention, the therapy subsystem 524 may alsoprovide for other types of stimulation, besides electrical stimulationdescribed above. In particular, in certain circumstances, it may beadvantageous to provide audio, visual, or tactile signals to thepatient, to provide somatosensory electrical stimulation to locationsother than the brain, or to deliver a drug or other therapeutic agent(either alone or in conjunction with stimulation).

Also the implantable neurostimulator device 110 contains a memorysubsystem 526 and the CPU 528, which can take the form of amicrocontroller. The memory subsystem is coupled to the detectionsubsystem 522 (e.g., for receiving and storing data representative ofsensed EEG or other signals and evoked responses), the therapy subsystem524 (e.g., for providing stimulation waveform parameters to the therapysubsystem for electrical stimulation), and the CPU 528, which cancontrol the operation of (and store and retrieve data from) the memorysubsystem 526. In addition to the memory subsystem 526, the CPU 528 isalso connected to the detection subsystem 522 and the therapy subsystem524 for direct control of those subsystems.

Also provided in the implantable neurostimulator device 110, and coupledto the memory subsystem 526 and the CPU 528, is a communicationsubsystem 530. The communication subsystem 530 enables communicationbetween the device 110 and the outside world, particularly an externalprogrammer 412 and a patient-initiating device 424, both of which aredescribed above with reference to FIG. 4. As set forth above, thedisclosed embodiment of the communication subsystem 530 includes atelemetry coil (which may be situated inside or outside of the housingof the implantable neurostimulator device 110) enabling transmission andreception of signals, to or from an external apparatus, via inductivecoupling. Alternative embodiments of the communication subsystem 530could use an antenna for an RF link or an audio transducer for an audiolink. Preferably, the communication subsystem 530 also includes a GMR(giant magnetoresistive effect) sensor to enable receiving simplesignals (namely the placement and removal of a magnet) from apatient-initiating device; this capability can be used to initiatesignal recording as will be described in further detail below.

If the therapy subsystem 524 includes the audio capability set forthabove, it may be advantageous for the communication subsystem 530 tocause the audio signal to be generated by the therapy subsystem 524 uponreceipt of an appropriate indication from the patient-initiating device(e.g., the magnet used to communicate with the GMR sensor of thecommunication subsystem 530), thereby confirming to the patient orcaregiver that a desired action will be performed, e.g. that an EEGrecord will be stored.

Several support components are present in the implantableneurostimulator device 110, including a power supply 532 and a clocksupply 534. The power supply 532 supplies the voltages and currentsnecessary for each of the other subsystems. The clock supply 534supplies substantially all of the other subsystems with any clock andtiming signals necessary for their operation, including a real-timeclock signal to coordinate programmed and scheduled actions and thetimer functionality used by the detection subsystem 522 that isdescribed in detail below.

In an embodiment of the invention, the therapy subsystem 524 is coupledto a thermal stimulator 536 and a drug dispenser 538, thereby enablingtherapy modalities other than electrical stimulation. These additionaltreatment modalities will be discussed further below. Any of thetherapies delivered by the therapy subsystem 524 is delivered to atherapy output at a specific site; it will be recognized that thetherapy output may be a stimulation electrode, a drug dispenser outlet,or a thermal stimulation site (e.g. Peltier junction or thermocouple) asappropriate for the selected modality.

It should be observed that while the memory subsystem 526 is illustratedin FIG. 5 as a separate functional subsystem, the other subsystems mayalso require various amounts of memory to perform the functionsdescribed above and others. Furthermore, while the implantableneurostimulator device 110 is preferably a single physical unit (i.e., acontrol module) contained within a single implantable physicalenclosure, namely the housing described above, other embodiments of theinvention might be configured differently. The neurostimulator 110 maybe provided as an external unit not adapted for implantation, or it maycomprise a plurality of spatially separate units each performing asubset of the capabilities described above, some or all of which mightbe external devices not suitable for implantation. Also, it should benoted that the various functions and capabilities of the subsystemsdescribed above may be performed by electronic hardware, computersoftware (or firmware), or a combination thereof. The division of workbetween the CPU 528 and the other functional subsystems may alsovary—the functional distinctions illustrated in FIG. 5 may not reflectthe partitioning and integration of functions in a real-world system ormethod according to the invention.

FIG. 6 depicts the previously illustrated hemisphere of a patient'sbrain 112 with a distal end of an exemplary cortical lead 610 positionedthereupon. In the illustrated embodiment, the cortical lead 610approaches the cingulate cortex 114 from a generally anterior direction;the lead 610 interfaces with the neurostimulator device 110 (FIG. 1) atits proximal end (not shown). The cortical lead may also be implantedfrom different approaches, depending on the surgeon's preference. Thedistal end of the cortical lead 610 bears four disc electrodes 612-618,each of which is in contact with or in close proximity to the surface ofthe cingulate gyrus 114. The entirety of the exemplary cortical lead isformed from biocompatible materials such as silicone and platinum.

FIG. 7 depicts the previously illustrated hemisphere of a patient'sbrain 112 with a distal end of an exemplary depth lead 710 implantedtherein. In the illustrated embodiment, the depth lead 710 interfaceswith the neurostimulator device 110 (FIG. 1) at its proximal end (notshown). The distal end of the depth lead 710 bears four ring electrodes712-718 preferably implanted into the gray matter of the cingulate gyrus114. As with the cortical lead 610, the depth lead 710 is fabricatedfrom biocompatible materials.

In the disclosed embodiment of the invention, the neurostimulator device110 is capable of receiving two leads, each with four electrodes. Onecortical lead 610 and one depth lead 710, two cortical leads, or twodepth leads can be used simultaneously to achieve the desired coverageof the cingulate gyrus 114 or other desired brain areas. It will berecognized that other embodiments of a system according to the inventionmay receive more leads, or leads and sensors in different forms thanthose specifically disclosed herein.

FIG. 8 illustrates details of the detection subsystem 52 (FIG. 5).Inputs from the electrodes 512-518 are on the left, and connections toother subsystems are on the right.

Signals received from the sensors 512-518 (as routed through the sensorinterface 520) are received in an input selector 810. The input selector810 allows the device to select which electrodes or other sensors (ofthe sensors 512-518) should be routed to which individual sensingchannels of the detection subsystem 522, based on commands receivedthrough a control interface 818 from the memory subsystem 526 or the CPU528 (FIG. 5). Preferably, when electrodes are used for sensing, eachsensing channel of the detection subsystem 522 receives a bipolar signalrepresentative of the difference in electrical potential between twoselectable electrodes. Accordingly, the input selector 810 providessignals corresponding to each pair of selected electrodes to a sensingfront end 812, which performs amplification, analog to digitalconversion, and multiplexing functions on the signals in the sensingchannels.

A multiplexed input signal representative of all active sensing channelsis then fed from the sensing front end 812 to a waveform analyzer 814.The waveform analyzer 814 is preferably a special-purpose digital signalprocessor (DSP) adapted for use with the invention, or in an alternativeembodiment, may comprise a programmable general-purpose DSP. In thedisclosed embodiment, the waveform analyzer has its own scratchpadmemory area 816 used for local storage of data and program variableswhen the signal processing is being performed. In either case, thesignal processor performs suitable measurement and detection methodsdescribed generally above and in greater detail below. Any results fromsuch methods, as well as any digitized signals intended for storagetransmission to external equipment, are passed to various othersubsystems of the device 110, including the memory subsystem 526 and theCPU 528 (FIG. 5) through a data interface 820. Similarly, the controlinterface 818 allows the waveform analyzer 814 and the input selector810 to be in communication with the CPU 528. The waveform analyzer 714is illustrated in detail in FIG. 9.

In the exemplary waveform analyzer illustrated in FIG. 9, theinterleaved digital data stream representing information from all of theactive sensing channels is first received by a channel controller 910.The channel controller applies information from the active sensingchannels to a number of wave morphology analysis units 912 and windowanalysis units 914. It is preferred to have as many wave morphologyanalysis units 912 and window analysis units 914 as possible, consistentwith the goals of efficiency, size, and low power consumption necessaryfor an implantable device. In a presently preferred embodiment of theinvention, there are sixteen wave morphology analysis units 912 andeight window analysis units 914, each of which can receive data from anyof the sensing channels of the sensing front end 812 (FIG. 8), and eachof which can be operated with different and independent parameters,including differing sample rates, as will be discussed in further detailbelow.

Each of the wave morphology analysis units 912 operates to extractcertain feature information from an input waveform. Similarly, each ofthe window analysis units 914 performs certain data reduction and signalanalysis within time windows. Output data from the various wavemorphology analysis units 912 and window analysis units 914 are combinedvia event detector logic 916. The event detector logic 916 and thechannel controller 910 are controlled by control commands 918 receivedfrom the control interface 818 (FIG. 8).

A “detection channel,” as the term is used herein, refers to a datastream including the active sensing front end 812 and the analysis unitsof the waveform analyzer 814 processing that data stream, in both analogand digital forms. It should be noted that each detection channel canreceive data from a single sensing channel; each sensing channelpreferably can be applied to the input of any combination of detectionchannels. The latter selection is accomplished by the channel controller910. As with the sensing channels, not all detection channels need to beactive; certain detection channels can be deactivated to save power orif additional detection processing is deemed unnecessary in certainapplications.

In conjunction with the operation of the wave morphology analysis units912 and the window analysis units 914, a scratchpad memory area 816 isprovided for temporary storage of processed data. The scratchpad memoryarea 816 may be physically part of the memory subsystem 526 (FIG. 5), oralternatively may be provided for the exclusive use of the waveformanalyzer 814 (FIG. 8). Other subsystems and components of a systemaccording to the invention may also be furnished with local scratchpadmemory, if such a configuration is advantageous.

A system according to the invention, particularly the neurostimulatordevice 110, is contemplated to be capable of multiple modalities oftherapy. In general, regular or scheduled therapy may be consideredadvantageous at certain times, and may be scheduled to operate inparallel with responsive therapy modes. Moreover, the neurostimulatordevice 110 is also gathering data to enable therapy refinement inconnection with the programmer 412 (FIG. 4) and other externalequipment. This process is illustrated in more detail in connection withFIG. 10.

A scheduler process maintained by the hardware of the implantableneurostimulator device 110 (FIG. 1), typically in the CPU 528 (FIG. 5),allows multiple tasks to be performed by the neurostimulator device 110in rapid sequence, effectively in parallel. In general, the schedulerallows subsidiary data collection, therapy delivery, and data analysisfunctions to be performed regularly. The scheduler is initially checked(step 1010). If it is time to collect data (step 1012)—as specified,generally, in a table of data collection times generated by theprogrammer 412 (FIG. 4)—then a record of data is collected (step 1014).Various types of sensor data, including electrographic signal waveforms,may be collected by a system according to the invention. If it is timeto deliver an episode of scheduled therapy (step 1016), then therapy isdelivered (step 1018). It should be noted that various types of therapymay be delivered, including but not limited to electrical stimulationand the administration of a dose of a therapeutic agent. As with datacollection times, therapy times may be uploaded from the programmer 412based on patient-specific observations made in the past or on some otherdesired dose schedule.

Inputs and other conditions are then observed (step 1020). A responsivetherapy decision is made (step 1022) based on the conditions observed bythe neurostimulator device 110, including but not limited toelectrographic activity, brain chemistry, temperature, other indicia ofphysiological conditions and metabolic rate, and patient intent (asindicated by a signal received from the patient initiating device 424(FIG. 4). Details on the conditions and information considered in atherapy decision are treated in more detail below with reference toFIGS. 11-17. If therapy is indicated, therapy is delivered (step 1024).

It should be noted that the scheduler function may also trigger othertypes of functions by the neurostimulator device 110, such asadministrative functions. The nature of these additional functions wouldbe understood by an engineer competent in designing real-time systems.

A number of lines of evidence identify the cingulate as a key region ofthe brain involved in major depression. Functional and structural brainneuroimaging in persons with major depressive disorder revealabnormalities in the anterior cingulate cortex (also referred to as the“ACC”). Anterior cingulate cortex volume is reduced in persons withmajor depression as demonstrated by MRI and by post-mortem study. PETscans show reduced cingulate activation in depressed persons performingcognitive tasks. Such abnormalities improve with relief of symptoms andworsen with worsening symptoms.

These observations suggest that modulation of cingulate metabolism byelectrical stimulation in a dynamic and responsive fashion could relievedepressive symptoms. Continuous recording of electrocorticographicactivity or of other biological markers enables monitoring of diseasestate and can direct the therapeutic electrical stimulation. Changes inmetabolic activity could prompt delivery of electrical stimulation thatis determined by the direction of change—that is stimulation that isprimarily excitatory can be applied when metabolism is inappropriatelylow and an inhibitory stimulation applied when metabolism is abnormallyactive. Stimulation can also be modified according to patient symptoms.Another advantage of this system is that applying stimulation only whenthe patient is symptomatic should extend battery life beyond the batterylife of a system providing continuous stimulation.

Referring now to FIG. 11, a specific method for treating depressionbegins by identifying baseline conditions (step 1110) in metabolic ratesand electrographic activity. Ideally, this step is performed while thepatient is feeling relatively symptom-free or when the patient is at hisor her usual level of depression. A system according to the inventionthen receives inputs (step 1112) and analyzes physiological activity(step 1114). If the patient's metabolic rates, as determined byobserving electrographic activity and other indicia of metabolic rate,are abnormally low (step 1116) in comparison to the baseline, excitatorytherapy is applied (step 1118). Excitatory therapy may includeelectrical stimulation having excitatory characteristics (or applied toa pathway that tends to excite the target area) or the release of atherapeutic agent having excitatory effects. If the patient's metabolicrates are abnormally high (step 1120) in comparison to the baseline,inhibitory therapy is applied (step 1122). Inhibitory therapy mayinclude electrical stimulation having inhibitory characteristics (orapplied to a pathway that tends to inhibit the target area) or therelease of a therapeutic agent having inhibitory effects.

Preferably, the method of treating depression includes the ability tocorrelate symptom data to observed inputs (step 1124). If the patient,using the initiating device 424 (FIG. 4) indicates that an episode ofdepression or an exacerbation of depressive symptoms is occurring, theneurostimulator device 110 can store a record of data to be analyzedeither by the CPU 528 (FIG. 5) or offline by a programmer 412 (FIG. 4)or other device. Later observations of the same or similar data willthen suggest an episode of depression, even when no patient input isreceived.

Bipolar disorder is associated with disturbances in attention, cognitionand impulse regulation thought to be related to disturbances in thecingulate gyrus. There are structural abnormalities in the cingulate inpersons with bipolar disorder, such as cellular and volumetricabnormalities. Functional MRI in persons with bipolar disorder showsdifferential activation in the cingulate depending upon whether thepatient is depressed or is experiencing elevated mood.

Similar to major depression, these findings imply that metabolism,electrical activity, and neurochemicals vary with mood and thatstimulation therapy applied to the cingulate will be most effective ifit can be modified according to the patient's symptoms. Mood changes inpersons with bipolar disorder may occur over months, weeks, days or evenhours. Therefore, a responsive system with modifiable stimulationparameters would appear to be of great interest as a treatment for thisdisorder.

In FIG. 12, a specific method for treating bipolar disorder begins byidentifying baseline conditions (step 1210) in metabolic rates andelectrographic activity. Ideally, this step is performed while thepatient is feeling relatively symptom-free or when the patient is at aknown level of depression or mania. A system according to the inventionthen receives inputs (step 1212) and analyzes physiological activity(step 1214). If the patient's metabolic rates, as determined byobserving electrographic activity and other indicia of metabolic rate,are abnormally low (step 1216) in comparison to the baseline, excitatorytherapy is applied (step 1218). Excitatory therapy may includeelectrical stimulation having excitatory characteristics (or applied toa pathway that tends to excite the target area) or the release of atherapeutic agent having excitatory effects. If the patient's metabolicrates are abnormally high (step 1220) in comparison to the baseline,inhibitory therapy is applied (step 1222). Inhibitory therapy mayinclude electrical stimulation having inhibitory characteristics (orapplied to a pathway that tends to inhibit the target area) or therelease of a therapeutic agent having inhibitory effects.

As with depression, the method of treating bipolar disorder preferablyincludes the ability to correlate observations to information ofinterest (step 1224), in this case time. As noted, bipolar disordertends to be cyclic and episodic, and advantages may be obtained byobserving patterns in detected symptoms, thereby enabling betterscheduled therapy (as illustrated in FIG. 10) or enhanced detection.Later observations of the same or similar data at similar times of day,week, or month would then suggest an episode of depression or mania,even when no patient input is received.

The cingulate cortex is a structure implicated in Obsessive-CompulsiveDisorder (OCD) and anxiety disorders. Animal models of anxiety andchronic behavioral stress reveal structural and metabolic changes in thecingulate cortex. Persons with anxiety disorders show abnormally highactivation of the cingulate cortex on fMRI during decision making. PETstudies in patients with OCD show variable changes in metabolismdepending on symptoms. Increased cingulate activation is observed inpersons with OCD and significant anxiety while those with compulsivehoarding have decreased cingulate activation. Electroencephalographicabnormalities are also described in persons with OCD.Magnetoencephalography performed in patients with OCD and extremeanxiety revealed paroxysmal rhythmic activity from the cingulate and inother regions of the limbic cortex.

The neurostimulator system described herein promises benefit to personswith OCD and anxiety disorders. Obsessive-compulsive disorder is dynamicin that symptom severity varies over the short-term and long-term.Symptom fluctuations must reflect changes in brain physiology, such asthe changes already observed in metabolism and electrical activity. Thecapacity of the device 110 to record from the cingulate will offeradvantages as electroencephalographic markers of disease activity arefurther defined and if other biological markers are discovered. Thisprovides further capacity to modify therapy in response to dynamicorganic processes and to provide responsive stimulation therapy with orwithout scheduled stimulation.

In FIG. 13, a specific method for treating anxiety andobsessive-compulsive disorders begins by receiving inputs (step 1310)and analyzing electrographic activity (step 1312).

If abnormal activation is observed (step 1314), typically by monitoringmetabolic rates or electrographic activity in comparison to a baselinelevel, a first therapy is applied (step 1316). Abnormally highactivation would trigger delivery of an inhibitory therapy, whileabnormally low activation would trigger excitatory therapy. As above,excitatory therapy may include electrical stimulation having excitatorycharacteristics (or applied to a pathway that tends to excite the targetarea) or the release of a therapeutic agent having excitatory effects,while inhibitory therapy may include electrical stimulation havinginhibitory characteristics (or applied to a pathway that tends toinhibit the target area) or the release of a therapeutic agent havinginhibitory effects.

If persistent abnormal neurologic activity is observed (step 1318), asecond therapy is applied (step 1320). The nature of the second therapymay be the same as or different from that of the first therapy, andwhether activation or inhibition is desired. The therapy desired in turnmay depend on whether the patient tends to exhibit OCD plus anxiety orcompulsive hoarding, to name the examples set forth above. Otherpatient-specific therapies may also be applicable and may depend onclinical observations. When possible, information is collected andcorrelated with observations to generate trends (step 1322) and improveperformance.

Post-Traumatic Stress Disorder (PTSD) is characterized by exaggeratedemotional and behavioral responses (hyperarousal) to stimuli associatedwith a traumatic experience. Many investigators propose that theanterior cingulate—a brain region that appears to be involved infear-conditioning—is dysfunctional in PTSD. Quantitative MRI reveals areduction in volume in the cingulate of persons with PTSD. FunctionalMRI investigations describe significantly less activation of theanterior cingulate gyrus than expected with presentation of stressfulstimuli. Observations that chronic behavioral stress inducesarchitectural and neurochemical changes in the cingulate gyrus alsosuggest that this structure may be an appropriate target for treatingPTSD.

An exemplary specific course of treatment for PTSD using an implantableneurostimulator device 110 is illustrated in FIG. 14. Initially, as PTSDcan be characterized by physiological changes, a first course ofnon-responsive therapy is applied (step 1410). This therapy may includeelectrical stimulation or any of the other treatment modalitiesdiscussed herein. This initial course of therapy is continued untilconditions change (step 1412) and improvement is observed.

Following the initial course of therapy and a change in conditions, theneurostimulator device processes inputs (step 1414) and analyzeselectrographic or other physiological brain activity (step 1416). Ifless activation is observed and a low level of electrographic or otherbrain activity is noted (step 1418), then a second therapy is applied(step 1420), typically excitatory. The nature of the therapy may varyfrom patient to patient. Finally, where possible, observations of lowactivation are correlated (step 1422) with stressful stimuli, asindicated by a patient using the initiating device 424 (FIG. 4) or byother means, thereby facilitating analysis of the correlation (either bythe device 110 or offline), enhancement of detection parameters, andimproved performance in the future.

PET scans in substance addicted individuals display metabolic activationof the cingulate during intoxication, craving and binging. In contrast,there is cingulate hypometabolism during withdrawal. A hypothesis isadvanced that changes in dopamine release and in dopamine receptors leadto changes in cingulate metabolic rates during intoxication, withdrawal,and craving. These observations suggest that disease activity can bemonitored directly from the cingulate and that modulating cingulatemetabolism by providing electrical stimulation therapy may lessen thebiologically based withdrawal and craving that leads to relapse.

In a system according to the invention, the hypometabolism observedduring withdrawal is sought to be treated as illustrated in FIG. 15.Initially, baseline metabolism conditions are observed (step 1510).Baseline conditions may include typical electrographic activity andother indicia of metabolism as discussed elsewhere in this document.Following that, the neurostimulator device 110 processes inputs (step1512) and analyzes electrographic activity (step 1514). If the patient'smetabolic rates, as determined by observing electrographic activity andother indicia of metabolic rate, are abnormally low (step 1516) incomparison to the baseline, excitatory therapy is applied (step 1518).As stated above, excitatory therapy may include electrical stimulationhaving excitatory characteristics (or applied to a pathway that tends toexcite the target area) or the release of a therapeutic agent havingexcitatory effects.

Preferably, observations of low metabolic rate are correlated (step1520) with the patient's symptoms by allowing input via initiatingdevice 424 (FIG. 4). In this manner, the patient can confirm episodes ofwithdrawal that are observed by the device 110 as periods of lowmetabolic rate, thereby validating the approach and enabling refinementof detection and therapy according to the invention. Also, the devicecan enable the patient to self-deliver therapy in response to symptomsof craving or withdrawal, much as patient-delivered devices delivernarcotic medications for pain. The device would be programmed in such away that the patient would not be able to deliver stimulation or othertherapy that could be harmful.

The anterior cingulate cortex (ACC) is a key region within the humanprefrontal cortex that has been shown to be dysfunctional inschizophrenic patients. PET scans demonstrate hypometabolism of thecingulate in patients with schizophrenia during cognitive processingtasks as well as in the resting state. Abnormalities in this functionalneuroimaging likely reflect underlying disturbances in cingulate anatomyand neurochemistry. Specific reductions in the volume of the cingulatecortex is described by MRI in patients with schizophrenia and is alsodetected by estimating total cell number in cytoarchitectonicallydefined areas from the prefrontal cortex. Neurochemical abnormalitiesdescribed in the cingulate cortex of persons with schizophrenia includea reduction the dopamine D2 receptors and dysfunction of excitatoryneurotransmitters such as glutamate.

Persons with schizophrenia have electroencephalographic abnormalities inthe cingulate cortex. Electrophysiological recordings from the cingulatecortex in animals and in persons with epilepsy indicate that backgroundactivity is similar to that of the hippocampus. However, persons withschizophrenia have poor synchronization of the EEG in the cingulate andabnormalities specifically in frequencies of about 40 Hz. These fastgamma frequencies cannot be detected by scalp EEG but are wellrepresented with intracranial recordings. Persons with schizophreniaalso have abnormal electrophysiological activity in the anteriorcingulate cortex during various cognitive activation tasks asdemonstrated by three-dimensional source location with low-resolutionelectromagnetic tomography (LORETA), including a significant increase indelta EEG activity.

This critical mass of research supports the premise that therapytargeted to the cingulate cortex will favorably influence schizophrenicsymptoms. Anatomical, neurochemical and electrophysiologicalabnormalities in the resting and activated states will providebiological markers for responsive therapy.

The neurostimulator system provides extensive coverage of the cingulatecortex from it's anterior to posterior extent, which enablesanatomically targeted therapy. Continuous recording enables detection ofchanges in electrographic activity and will provide information criticalto refining our understanding of the functional disturbances of thecingulate in this disease state. Accumulating data regarding theelectrophysiology of the cingulate in schizophrenia will also be key tooptimizing electrical stimulation therapy—both to correct any basalabnormalities as well as to respond to event related electricaldisturbances.

In FIG. 16, a specific method for treating schizophrenia begins byreceiving inputs (step 1610) and analyzing electrographic activity (step1612). If the patient's metabolic rate is low (step 1614), or poorsynchronization is observed (step 1616), or abnormal gamma activity isobserved (step 1618), or abnormal delta activity is observed (step1620), then the totality of circumstances is analyzed to determinewhether therapy is indicated (step 1622). If so, then therapy is applied(step 1624), and may be either excitatory or inhibitory, as clinicalcircumstances dictate.

In a system according to the invention, synchronization (or the lackthereof), and activity in various frequency bands may be determined withan appropriately configured wave morphology analysis unit, such as onethat analyzes the duration and amplitude of signal half waves. See,e.g., U.S. Pat. No. 6,810,285 to Pless et al. entitled “SEIZURE SENSINGAND DETECTION USING AN IMPLANTABLE DEVICE,” issued Oct. 26, 2004. Thedisclosure of the application on which that patent issued is herebyincorporated by reference as though set forth in full herein. Such adevice can respond to the fluctuating symptoms of schizophrenia, such ashallucinations and delusions. This device also provides a distinctadvantage to pharmacological therapy. Failure of therapy in persons withschizophrenia is often related to non-compliance. This device removesthe need for the patient to remember and be willing to take medicationsmultiple times per day.

Dysfunction of the cingulate cortex is implicated in the socialdisability associated with autism and pervasive developmental delay.Persons with autism have qualitative impairment in social interactionand communication. The cingulate is believed to be essential for highercognitive function and in the expression and recognition of affect.Cytoarchitectonic changes are described in the cingulate cortex as wellas the hippocampus, subiculum and entorhinal cortex of persons withautism studied post-mortem. Significant reductions in metabolic activityin cingulate gyri are visualized in persons with autism spectrumdisorders imaged by PET scans. Stimulation over the cingulate cortexcould activate those centers mediating these social behaviors.

There is a high prevalence of epilepsy in persons with autism.Epileptiform discharges are described in medial frontal regions inpersons with autism. Similar to frontal lobe epilepsy, these dischargesoften activate with sleep. Some persons with autism improve cognitivelywhen treated with antiepileptic drugs. A system according to theinvention can detect and treat such abnormal electrographic dischargesvia cortical electrodes placed over the cingulate cortex, as more fullydescribed in U.S. Pat. No. 6,597,954 to Pless et al. entitled “SYSTEMAND METHOD FOR CONTROLLING EPILEPTIC SEIZURES WITH SPATIALLY SEPARATEDDETECTION AND STIMULATION ELECTRODES,” issued Jul. 22, 2003 and entitled“System and Method for Controlling Epileptic Seizures with SpatiallySeparated Detection and Stimulation Electrodes,” the disclosure of whichis hereby incorporated by reference as though set forth in full herein,and others.

An exemplary method according to the invention for treating autism isillustrated in FIG. 17, on the premise that a short-term depression inmetabolic rate may be indicative of increased symptoms. Initially, asautism and certain developmental disorders are characterized byphysiological changes, a first course of non-responsive therapy isapplied (step 1710). This therapy may include electrical stimulation orany of the other treatment modalities discussed herein. This initialcourse of therapy is continued until conditions change (step 1712) andimprovement is observed.

Following the initial course of therapy and a change in conditions, theneurostimulator device processes inputs (step 1714). Then, essentiallyin parallel, electrographic activity is analyzed (step 1716) andmetabolic rate is analyzed (step 1718). If the metabolic rate isabnormally low (step 1720), a second course of therapy, typicallyexcitatory, is provided (step 1722) to correct the level of function. Atsubstantially the same time, if epileptiform electrographic activity isobserved (step 1724), then an appropriate third therapy is delivered(step 1726). For details on an exemplary method for detecting andtreating undesired epileptiform activity, see U.S. Pat. No. 6,810,285,referenced above.

Referring now to FIG. 18, in addition to traditional biphasic pulsewaveforms used for neurostimulation, other wave morphologies may haveadvantageous applications herein. A sinusoidal stimulation signal 1810can be produced and used for non-responsive or responsive brainstimulation according to the invention. In general, sinusoidal andquasi-sinusoidal waveforms may be delivered at low frequencies to havean inhibitory effect, where low frequencies are 0.5 to 10 Hz deliveredfor 0.05 to 60 minutes at a time. Such waveform may be applied as aresult of determining that inhibition is desired on a scheduled basis,or after conditions indicate that responsive stimulation should beapplied. Higher frequency sinusoidal or quasi-sinusoidal waveforms maybe used for activation. Amplitudes in the range of 0.1 to 10 mA wouldtypically be used, but attention to safe charge densities is importantto avoid neural tissue damage (where a conservative limit is 25 μC/cm²per phase). It should be noted that the inhibitory and activatingfunctions of various sinusoidal stimulation parameters may vary whenapplied to different parts of the brain; the above is merely exemplary.

Sinusoidal and quasi-sinusoidal waveforms presented herein would beconstructed digitally by the therapy subsystem 524 (FIG. 5) of theimplantable neurostimulator device 110. As a result, the sinusoid 1810is really generated as a stepwise approximation, via a series of smallsteps 1812. The time between steps is dependent upon the details of thewaveform being generated, but an interval of 40 microseconds has beenfound to be a useful value. It is anticipated that the stair stepwaveform 1812 may be filtered to arrive at a waveform more similar to1814, which would allow for longer periods of time between steps andlarger steps. Likewise, for the waveforms 1816, 1820, and 1822(described below), it is assumed that they may be created with a seriesof steps notwithstanding their continuous appearance in the figures.

A truncated ramp waveform 1814 is also possible, where the rate of theramp, the amplitude reached and the dwell at the extrema are allselectable parameters. The truncated ramp has the advantage of ease ofgeneration while providing the physiological benefits of a sinusoidal orquasi-sinusoidal waveform.

A variable sinusoidal waveform 1816 where the amplitude and frequencyare varied while the waveform is applied is also illustrated. The rateand amplitude of the variation may be varied based upon a predefinedplan, or may be the result of the implanted neurostimulator sensingsignals from the brain during application or between applications of thewaveform, and adjusting to achieve a particular change in the sensedsignals. The variable waveform 1816 is illustrated herein as having apositive direct current component, but it should be noted that thiswaveform, as well as any of the others described herein as suitable foruse according to the invention, may or may not be provided with a directcurrent component as clinically desired.

Waveforms 1820 and 1822 depict variations where the stimulating waveformis generated having a largely smooth waveform, but having the additionalfeature where the interval between waveforms is set by varying aselectable delay, as would be used with the traditional biphasic pulsewaveforms described previously. In waveform 1820, the stimulatingwaveforms are segments of a sine wave separated in time (of course thesame technique could be used for the truncated ramp, or other arbitrarymorphologies). Waveform 1822 shows a variation where the derivative intime of the waveform approaches zero as the amplitude approaches zero.The particular waveform 1822 is known as a haversine pulse.

Although the term “haversine pulse” is useful to describe the waveformof 1822, it should be noted that all of the waveforms represented inFIG. 18 are considered herein to be generally “non-pulsatile,” incontrast with waveforms made up of traditional discontinuous (e.g.square) pulses. As the term is used herein, “non-pulsatile” can also beapplied to other continuous, semi-continuous, discontinuous, orstepwise-approximated waveforms that are not exclusively defined bymonophasic or biphasic square pulses.

In the disclosed embodiment, the default stimulation behavior providedby a neurostimulator according to the invention is to stimulate withcharge-balanced biphasic pulses. This behavior is enforced bystimulation generation hardware that automatically generates a symmetricequal-current and equal-duration but opposite-polarity pulse as part ofevery stimulation pulse; the precise current control enabled by thepresent invention makes this approach possible. However, theneurostimulator is preferably programmable to disable the automaticcharge balancing pulse, thereby enabling the application of monophasicpulses (of either polarity) and other unbalanced signals.

Alternatively, if desired, charge balancing can be accomplished insoftware by programming the neurostimulator to specifically generatebalancing pulses or signals of opposite phase. Regardless of whethercharge balancing is accomplished through hardware or software, it is notnecessary for each individual pulse or other waveform component to becounteracted by a signal with identical morphology and opposingpolarity; symmetric signals are not always necessary. It is alsopossible, when charge balancing is desired, to continuously orperiodically calculate the accumulated charge in each direction andensure that the running total is at or near zero over a relatively longterm and preferably, that it does not exceed a safety threshold even fora short time.

To minimize the risks associated with waveforms that are eitherunbalanced or that have a direct current component, it is advantageousto use electrodes having enhanced surface areas. This can be achieved byusing a high surface area material like platinum black or titaniumnitride as part or all of the electrode. Some experimenters have usediridium oxide advantageously for brain stimulation, and it could also beused here. See Weiland and Anderson, “Chronic Neural Stimulation withThin-Film, Iridium Oxide Electrodes,” IEEE Transactions on BiomedicalEngineering, 47: 911-918 (2000).

An implantable version of a system according to the inventionadvantageously has a long-term average current consumption on the orderof 10 microamps, allowing the implanted device to operate on powerprovided by a coin cell or similarly small battery for a period of yearswithout need for replacement. It should be noted, however, that asbattery and power supply configurations vary, the long-term averagecurrent consumption of a device according to the invention may also varyand still provide satisfactory performance.

It should be observed that while the foregoing detailed description ofvarious embodiments of the present invention is set forth in somedetail, the invention is not limited to those details and an implantableneurostimulator or neurological disorder detection device made accordingto the invention can differ from the disclosed embodiments in numerousways. In particular, it will be appreciated that embodiments of thepresent invention may be employed in many different applications toresponsively treat psychiatric disorders. It will be appreciated thatthe functions disclosed herein as being performed by hardware andsoftware, respectively, may be performed differently in an alternativeembodiment. It should be further noted that functional distinctions aremade above for purposes of explanation and clarity; structuraldistinctions in a system or method according to the invention may not bedrawn along the same boundaries. Hence, the appropriate scope hereof isdeemed to be in accordance with the claims as set forth below.

1. An implantable apparatus for treating a psychiatric disorder in ahuman patient by selectively applying therapy, the apparatus comprising:an electrode array comprising a plurality of electrodes designed for andintended to be deployed so that the electrodes can be used to deliverstimulation to substantially any area of the cingulate cortex; a therapysubsystem coupled to the electrode array, wherein the therapy subsystemis operative to selectively initiate delivery of a therapy to at leastone of the electrodes in the electrode array; a detection subsystemcoupled to at least one sensor, wherein the detection subsystem isoperative to receive and process a signal corresponding to acharacteristic of the psychiatric disorder and generated by the at leastone sensor; a processor operative to identify a detected event in thesignal generated by the at least one sensor and to cause the therapysubsystem to initiate application of the therapy through at least one ofthe electrodes in the electrode array.
 2. The implantable apparatus ofclaim 1, wherein the psychiatric disorder is depression, bipolardisorder, anxiety disorder, obsessive-compulsive disorder,post-traumatic stress disorder, addiction, schizophrenia, autism, or adevelopmental disorder.
 3. The implantable apparatus of claim 1, whereinthe at least one sensor comprises at least one electrode, and the atleast one electrode is designed for and intended to be situated at or inthe vicinity of the cingulate gyrus of the patient's brain.
 4. Theimplantable apparatus of claim 1, wherein the therapy compriseselectrical stimulation.